chr19-17824811-CA-C

Position:

• chr19-17824811-CA-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000215.4(JAK3):​c.*1931del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 194,902 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0079 (1 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.337

Genes affected

JAK3 (HGNC:6193): (Janus kinase 3) The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 19-17824811-CA-C is Benign according to our data. Variant chr19-17824811-CA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328461.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00664 (1012/152304) while in subpopulation NFE AF= 0.0104 (707/68028). AF 95% confidence interval is 0.00976. There are 6 homozygotes in gnomad4. There are 442 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.*1931del		3_prime_UTR_variant	24/24	ENST00000458235.7
JAK3	XM_047438786.1	c.*1931del		3_prime_UTR_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.*1931del		3_prime_UTR_variant	24/24	5	NM_000215.4	P1
JAK3	ENST00000527031.5	n.2777del		non_coding_transcript_exon_variant	14/14	2
JAK3	ENST00000696967.1	n.4483del		non_coding_transcript_exon_variant	19/19

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1011 AN: 152186 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00789 AC: 336 AN: 42598 Hom.: 1 Cov.: 0 AF XY: 0.00801 AC XY: 159 AN XY: 19842

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00482

GnomAD4 genome AF: 0.00664 AC: 1012 AN: 152304 Hom.: 6 Cov.: 33 AF XY: 0.00593 AC XY: 442 AN XY: 74482

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00300 Hom.: 0

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe combined immunodeficiency disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

JAK3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147498283; hg19: chr19-17935620;